8.1b Antifungal Agents

What is the overview of antifungal agents?

• Many target the cell membrane or cell wall

• Some are fungistatic (inhibit growth rather than kill)

• Severe infections occur mainly in immunocompromised patients (e.g. disease or chemotherapy)

What are azoles and their key features?

• Azoles inhibit ergosterol synthesis by blocking cytochrome P450-dependent 14α-lanosterol demethylation

• Ketoconazole largely replaced due to side effects

• Itraconazole safer, broader activity (Candida, Cryptococcus, Aspergillus, dermatophytes); needs food and acid for max absorption

• Fluconazole has narrower spectrum, treats Candida and Cryptococcus, used for prophylaxis in immunosuppressed patients

Give key clinical points for voriconazole and posaconazole?

• Voriconazole broad-spectrum; active vs Candida, Aspergillus, molds; 1st line for aspergillosis

• Posaconazole broadest azole; oral only, take with food; active vs yeasts and molds; used for thrush and prophylaxis; fewer interactions

• Azoles may promote hepatitis (rare) and have specific drug interactions, requiring monitoring

What are the mechanism, action, toxicity, and main agents of polyenes?

• Bind ergosterol in fungal cell membranes

• Increase membrane permeability causing leakage

• Fungicidal in action

• Toxicity due to weak cholesterol binding

• Main agents Nystatin (topical) and Amphotericin B (systemic)

What are the main uses, absorption properties, and administration methods of Nystatin?

Nystatin is used as a ________ ________ for the treatment of ________ ________; it is poorly absorbed from the ________________ _____ so has limited ________ ______; administration methods include “ _____ __ _______” or “ _____ ___ ____”.

Nystatin is used as a topical agent for the treatment of oral Candida; it is poorly absorbed from the gastrointestinal tract so has limited toxicity issues; administration methods include “swish and swallow” or “swish and spit”.

What are the formulation, toxicity, and spectrum of activity of Amphotericin B?
Only available as an ____________ – colloidal suspension with ________ ____________ due to poor water solubility
Binds serum lipoproteins, penetrates poorly into ___ and other fluids
Causes _____________, ____, and infusion reactions – fever, chills, nausea, myalgias; slow infusion required
Lipid-based formulations (________) reduce toxicity
Broad-spectrum activity – ______, _________ ___, ___________ ___, molds including __________

Only available as an intravenous – colloidal suspension with sodium deoxycholate due to poor water solubility
Binds serum lipoproteins, penetrates poorly into CSF and other fluids
Causes nephrotoxicity, anemia, and infusion reactions – fever, chills, nausea, myalgias; slow infusion required
Lipid-based formulations (liposomes) reduce toxicity
Broad-spectrum activity – yeasts, Candida spp., Cryptococcus spp., molds including Aspergillus

What is the mechanism, formulation, activity, and key features of Allylamines such as Terbinafine?
Inhibit __________ __________ blocking __________ synthesis in the fungal cell membrane. Key example is __________. Available in both ______ and ______ formulations – active against __________ that cause skin and nail infections; generally active against __________ __________. Reserved for infections unresponsive to other agents; not for __________ infections; therapy usually lasts ___ months. With oral use, drug distributes to skin, nails, and fat – long half-life up to ___ hours. Common adverse effects involve the _______________________ ______.

Inhibit squalene epoxidase blocking ergosterol synthesis in the fungal cell membrane. Key example is Terbinafine. Available in both oral and topical formulations – active against dermatophytes that cause skin and nail infections; generally active against Candida albicans. Reserved for infections unresponsive to other agents; not for systemic infections; therapy usually lasts 3 months. With oral use, drug distributes to skin, nails, and fat – long half-life up to 400 hours. Common adverse effects involve the gastrointestinal tract.